Human infections with Lentiviridae, such as HIV, and Flaviviridae, such as HCV, pose significant challenges to global health. Although potent anti-HCV drugs are in clinical development and response rates to interferon-based regimens have improved with the inclusion of protease inhibitors (PI), resistance, drug-drug interactions, and cumulative toxicity continue to pose challenges. More effective antiviral strategies are therefore still in need to combat the HCV pandemics. In addition, novel antiviral strategies are needed for inclusion in salvage regimens for treating HIV in patients failing highly active antiretroviral therapy (HAART) due to resistant virus.